PONE-D-19-25405

Prevalence and effects of gastro-oesophageal reflux during spirometry in subjects undergoing reflux assessment

PLOS ONE

Dear Dr. Jerry Zhou,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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Additional Editor Comments (if provided):

This is an interesting manuscript and the authors should follow the reviewer' suggestions in order to improve the impact of the manuscript.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This study demonstrates GOR may result in very mild physiologic changes but not clinically significant changes in the patients studied. The authors imply specific changes despite not proven by statistics.

Reviewer #2: The present work was aimed to show the occurrence of gastro-oesophageal reflux (GOR) during or soon after spirometry (i.e.: forced expiratory maneuver following full inspiration to total lung capacity) and to assess the potential consequences of in-expiratory effort-related GOR in terms of subsequent respiratory functional results and their variability.

The rational is that in individuals who potentially may have gastro-oesophageal reflux disease (GORD), as suggested by peculiar symptoms or anatomic-functional predisposing conditions, the increased positive pressure gradient occurring during in-expiratory efforts between abdomen and thorax may induce distal or even proximal acid reflux causing reflex bronchoconstriction or upper airway stimulation with subsequent increase in airflow resistance.

In this cohort of subjects with high probability of having GORD, the Authors found that GOR was present during or following spirometry in almost half of the subjects (26/58). In contrast with subjects without GOR during or following spirometry, those with GOR showed in the subsequent set of spirometry a significant reduction of some functional parameters, suggesting the occurrence of the GOR-related airflow obstruction.

In addition, the results show that in 39 subjects over 58 suspected of GORD who were diagnosed as having GORD by standard criteria based on 24-hours oesophageal pH monitoring, about 50% (20/39) exhibited spirometry-induced GOR and the resting 50% (19/39) not. Conversely, in 19 subjects who did not have GORD, 6/19 (about one/third) exhibited spirometry-induced GOR and 13/19 not. Thus, repeated spirometry seems not useful to increase the diagnosis of GORD.

General comments

The presence of GOR during spirometry is not a novelty and in fact deflation-related peak expiratory flows occurring near residual volume at the end of maximal expiratory maneuvers has been suggested as a marker of GOR (see Lavorini et al. Chest 2011;140:690).

The new findings of this work are the more frequent occurrence of GOR throughout 10 minutes after spirometry than during spirometry and the mild reduction of some functional indices (such as PEF and FEV1) in the subsequent set of spirometry.

Surprisingly GOR was recorded also during slow inspiration toward TLC before the maximal forced expiration.

The methods to assess GOR are up to date.

The numbers in the tables 1 and 2 are difficult to follow and sometimes do not fit with the text. Please check it.

The statistics are adequate.

Minor comments

I do not think these findings may explain the paradoxical increase of airflow obstruction after a bronchodilator test performed to assess the reversibility of baseline airway obstruction and I will skip this sentence from the discussion.

Some English mistakes here and there need to be amended.

**********

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-25405R1

Prevalence and effects of gastro-oesophageal reflux during spirometry in subjects undergoing reflux assessment

PLOS ONE

Dear Dr. Jerry Zhou,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The authos should revise the manuscript following reviewers' suggestions.

In addition, I found old papers cited in the reference list concerning the mechanisms of association between GOR and bronchospasm/asthma and, in particular, I would add some sentences about the role of neurogenic inflammation as a main mechanism of bronchoconstriction due to airway acidification (protons-induced bronchoconstriction). I suggest to update the reference list.

We would appreciate receiving your revised manuscript by February 4th. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Fabio Luigi Massimo Ricciardolo

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer 1:

This study demonstrates GOR may result in very mild physiologic changes but not clinically significant changes in the patients studied. The authors imply specific changes despite not proven by statistics.

Reviewer 2:

 

The present work was aimed to show the occurrence of gastro-oesophageal reflux (GOR) during or soon after spirometry (i.e.: forced expiratory maneuver following full inspiration to total lung capacity) and to assess the potential consequences of in-expiratory effort-related GOR in terms of subsequent respiratory functional results and their variability.

The rational is that in individuals who potentially may have gastro-oesophageal reflux disease (GORD), as suggested by peculiar symptoms or anatomic-functional predisposing conditions, the  increased positive pressure gradient occurring during in-expiratory efforts between abdomen and thorax may induce distal or even proximal acid reflux causing reflex bronchoconstriction or upper airway stimulation with subsequent increase in airflow resistance.

In this cohort of subjects with high probability of having GORD, the Authors found that GOR was present during or following spirometry in almost half of the subjects (26/58). In contrast with subjects without GOR during or following spirometry, those with GOR showed in the subsequent set of spirometry a significant reduction of some functional parameters, suggesting the occurrence of the GOR-related airflow obstruction.

In addition, the results show that in 39 subjects over 58 suspected of GORD who were diagnosed as having GORD by standard criteria based on 24-hours oesophageal pH monitoring, about 50% (20/39) exhibited spirometry-induced GOR and the resting  50% (19/39) not. Conversely, in 19 subjects who did not have GORD, 6/19 (about one/third) exhibited spirometry-induced GOR and 13/19 not. Thus, repeated spirometry seems not useful to increase the diagnosis of GORD.

General comments

The presence of GOR during spirometry is not a novelty and in fact deflation-related peak expiratory flows occurring near residual volume at the end of maximal expiratory maneuvers has been suggested as a marker of GOR (see Lavorini et al. Chest 2011;140:690).

The new findings of this work are the more frequent occurrence of GOR throughout 10 minutes after spirometry than during spirometry and the mild reduction of some functional indices (such as PEF and FEV1) in the subsequent set of spirometry.

Surprisingly GOR was recorded also during slow inspiration toward TLC before the maximal forced expiration.

The methods to assess GOR are up to date.

The numbers in the tables 1 and 2 are difficult to follow and sometimes do not fit with the text. Please check it.

The statistics are adequate.

Minor comments

I do not think these findings may explain the paradoxical increase of airflow obstruction after a bronchodilator test performed to assess the reversibility of baseline airway obstruction and I will skip this sentence from the discussion.

Some English mistakes here and there need to be amended.

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Prevalence and effects of gastro-oesophageal reflux during spirometry in subjects undergoing reflux assessment

PONE-D-19-25405R2

Dear Dr. Jerry Zhou,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Fabio Luigi Massimo Ricciardolo

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Author responses are appropriate and ms acceptable for publication. The ms will serve as a guide to pulmonologists when interpreting pulmonary function studies in patients with GERD

Reviewer #2: General comments

The amended version of this work is definitively improved, more easily readable and better written than the original paper.

I do not have more questions or criticisms to rise.

The main practical advice following the results of this study is that in patients with baseline obstructive ventilatory defect, knowing to have GORD or predisposing conditions to GOR, the spirometric response to a subsequent test of bronchial responsiveness using short-acting bronchodilators (if required) should be assessed after an interval of time longer than 10 minutes (20 or better 30 min) to avoid spurious results.

Perhaps this suggestion could be added at the end of discussion section if Authors agree.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Arthur F Gelb MD

Reviewer #2: No